BACKGROUND & AIMS: Thrombocytopenia is common among patients with hepatitis C virus (HCV) infection and advanced fibrosis or cirrhosis, limiting initiation and dose of peginterferon-α (PEG) and ribavirin (RBV) therapy. The phase 3 randomized, controlled studies, Eltrombopag to Initiate and Maintain Interferon Antiviral Treatment to Benefit Subjects with Hepatitis C-Related Liver Disease (ENABLE)-1 and -2, investigated the ability of eltrombopag to increase numbers of platelets in patients, thereby allowing them to receive initiation or maintenance therapy with PEG and RBV.

METHODS: Patients with HCV infection and thrombocytopenia (platelets <75,000/μL) who participated in ENABLE-1 (n=715) or ENABLE-2 (n=805), from approximately 150 centers in 23 countries, received open-label eltrombopag (25-100 mg daily) for ≤9 weeks. Patients whose platelet counts reached the predefined minimal threshold for initiation of PEG and RBV therapy (95% from ENABLE-1 and 94% from ENABLE-2) entered the antiviral treatment phase, and were randomly assigned (2:1) to groups that received eltrombopag or placebo along with antiviral therapy (24 or 48 weeks, depending on HCV genotype). The primary endpoint was sustained virologic response (SVR) 24 weeks after completion of antiviral therapy.

RESULTS: More patients who received eltrombopag than placebo achieved SVRs (ENABLE-1: eltrombopag 23%, placebo 14% [P=.0064]; ENABLE-2: eltrombopag 19%, placebo 13% [P=.0202]). PEG was administered at higher doses, with fewer dose reductions, in the eltrombopag groups of each study compared with the placebo groups. More patients who received eltrombopag than placebo maintained platelets ≥50,000/μL throughout antiviral treatment (ENABLE-1: 69% vs 15%; ENABLE-2: 81% vs 23%). Adverse events were similar between groups, with the exception of hepatic decompensation (both studies: eltrombopag, 10%; placebo, 5%) and thromboembolic events, which were more common in the eltrombopag group of ENABLE-2.

Centre for Immunity, Infection and Evolution, University of Edinburgh, Scotland, UK.

Abstract

The 2005 consensus proposal for the classification of hepatitis C virus (HCV) presented an agreed and uniform nomenclature for HCV variants and the criteria for their assignment into genotypes and subtypes. Since its publication, the available dataset of HCV sequences has vastly expanded through advancement in nucleotide sequencing technologies and an increasing focus on the role of HCV genetic variation in disease and treatment outcomes. The current study represents a major update to the previous consensus HCV classification, incorporating additional sequence information derived from over 1,300 (near-)complete genome sequences of HCV available on public databases in May 2013. Analysis resolved several nomenclature conflicts between genotype designations and using consensus criteria created a classification of HCV into seven confirmed genotypes and 67 subtypes. There are 22 additional complete coding region sequences of unassigned subtype. The study additionally describes the development of a Web resource hosted by the International Committee for Taxonomy of Viruses (ICTV) that maintains and regularly updates tables of reference isolates, accession numbers, and annotated alignments (http://talk.ictvonline.org/ictv_wikis/w/sg_flavi/default.aspx). The Flaviviridae Study Group urges those who need to check or propose new genotypes or subtypes of HCV to contact the Study Group in advance of publication to avoid nomenclature conflicts appearing in the literature. While the criteria for assigning genotypes and subtypes remain unchanged from previous consensus proposals, changes are proposed in the assignment of provisional subtypes, subtype numbering beyond "w," and the nomenclature of intergenotypic recombinant. Conclusion: This study represent an important reference point for the consensus classification of HCV variants that will be of value to research working in clinical and basic science fields. (Hepatology 2013;).

Several simple noninvasive scoring systems have been developed using routinely measured clinical and laboratory variables to differentiate nonalcoholic fatty liver disease (NAFLD) with and without advanced fibrosis (NEJM JW Gastroenterol Dec 4 2009). However, no studies to date have determined if these scoring systems predict long-term outcomes.

Now, researchers have examined this issue in a retrospective study of 320 well-characterized patients with biopsy-proven NAFLD treated in multiple, international centers. Based on calculations of four validated scoring systems, the NAFLD fibrosis score, the aspartate aminotransferase (AST)/platelet ratio index, the FIB-4 score, and the BARD score, patients were categorized into low-, intermediate-, and high-risk groups. Outcomes included liver-related complications, transplantation, or death.

Fourteen percent of patients developed liver-related complications, and 13% died or underwent liver transplantation during a median follow-up of 104.8 months (range, 3–317 months). Characterizations of intermediate and high risks versus low risk were associated with increased likelihood of liver-related complications using the NAFLD fibrosis score (adjusted hazard ratios, 7.7 and 34.2, respectively), the AST/platelet ratio index (aHRs, 8.8 and 20.9), and the BARD score (aHRs, 6.2 and 6.6). Characterizations of intermediate and high risks versus low risk were associated with increased likelihood of death or transplantation only using the NAFLD fibrosis score (aHRs, 4.2 and 9.8).

Comment

Despite the typical inherent biases associated with the retrospective study design, these findings demonstrate that previously validated, simple, noninvasive nonalcoholic fatty liver disease scoring systems are able to predict long-term, liver-related complications and — in the case of the NAFLD fibrosis score — long-term survival and need for liver transplantation. With further validation of these findings, clinicians can use a scoring system such as the NAFLD fibrosis score to counsel NAFLD patients, and researchers can use it as the study endpoint in NAFLD treatment trials.

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/liv.12363

In HCV genotype 1-infected patients with HIV co-infection, tritherapy [HCV protease inhibitors (PIs) plus peg-interferon and ribavirin] has been shown to have an increased rate of sustained virological response. However, complex drug-to-drug interactions and tolerability issues remain a concern.

Methods

Under the auspices of four French scientific societies of medicine, a committee was charged of establishing guidelines on the use of first-generation HCV PIs in these patients. This scientific committee based its work on preliminary results from tritherapy clinical trials in co-infected patients and, since data on these patients are still scarce, on the statements already made by the French Association for the Study of the Liver (AFEF)

on the use of tritherapy in HCV mono-infected patients, written in May 2011 and updated in 2012. Each AFEF guideline concerning HCV mono infection was examined in order to determine whether it could be used in the context of HIV/HCV coinfection.

Results

These guidelines are addressed for the treatment of coinfected patients with various profiles, including treatment-naïve or patients with failure to previous bitherapy and mention those patients for whom tritherapy should start or those for whom it should be delayed. Preliminary results of triple therapy as well as factors associated to virological response are also discussed. Other issues include virological monitoring, clinical and virological criteria to stop therapy, practical treatment management, treatment adherence and the management of side effects and interactions with antiretroviral drugs. These guidelines were submitted for critical review to independent experts.

Gastroenterology Division, Catholic University of the Sacred Heart of Rome, School of Medicine, Rome, Italy 1Gastroenterology Division, University of Palermo, Palermo, Italy

1Gastroenterology Division, University of Palermo, Palermo, Italy

The revolution of hepatitis C virus (HCV) infection treatment started in the early 1990s, with the introduction of interferon (IFN) alpha, but the best results have been achieved in the recent years. Far from the possibility to be preempted by vaccination, hepatitis C is not easy to cure in every patient. The combined therapy with pegylated-IFN (PEG-IFN) plus ribavirin (RBV), which represented the standard of care available up to now, led to suboptimal results and was almost always poorly tolerated, requiring dose reduction or treatment discontinuation. Furthermore, infection recurrence was around the corner, and patients who partially responded or did not respond to treatment had to face the frustrating concept to have no alternative therapeutic option.

The need to improve treatment results, which is particularly heartfelt when special population of patients are considered, such as liver transplant recipients and cirrhotics, pushed the scientific community to struggle for the development of new drugs. The new direct acting antivirals (DAAs) are active on specific viral components and include non-structural 3/4A (NS3/4A) protease inhibitors, nucleoside/ nucleotide analogue and non-nucleoside inhibitors of the HCV RNA-dependent RNA polymerase (RdRp), inhibitors of the HCV non-structural protein 5A (NS5A), and cyclophylin inhibitors1. Telaprevir and Boceprevir are the first NS3/4A protease inhibitors, approved in 2011 for the treatment of genotype 1 patients2,3. However, the first era of DAAs will end soon, more quickly then expected. The clinical experience with Telaprevir and Boceprevir has not produced in facts fully satisfactory results. Up to 86% of genotype 1 non-cirrhotic patients may achieve a sustained virological response (SVR), (SPRINT-2, RESPOND-2, ADVANCE, REALIZE Trials4-7), however, strong efforts due to poor tolerability and adverse events, and 24-48 weeks of treatment are needed. Moreover, the efficacy is lower in patients experienced to treatment. Nevertheless, treatment administration is not simple and requires the intake of a number of daily pills, up to 12, in addition to RBV. Cirrhotic patients have less benefits and experience more life-threatening adverse events8. Data about liver transplanted patients with HCV recurrence clearly show low SVR rates, increased prevalence of acute rejection and interaction with immunosuppressants, the main factor that has made improbable their future use in these patients9-12. Finally, Telaprevir and Boceprevir are not approved for the treatment of genotype 2 and 3 patients, whose standard of care still remains the PEG-IFN plus RBV combination therapy.

For all these reasons, several second generation DAAs are being tested. The most promising news is that HCV treatment is clearly moving toward the burial of PEG-IFN. According to the most recent scientific reports, selected patients (and hopefully every patient in the near future) will benefit of PEG-IFN free regimens, with very good results. Three recent trials, the FISSION13, FUSION and POSITRON14 (Table 1) assessed the rate of SVR at 12 weeks (SVR 12) obtained after the end of treatment with the NS5B polymerase inhibitor Sofosbuvir in genotype 2 or 3 naïve, experienced to treatment or IFN intolerant patients. The results were exciting for genotype 2 patients, with SVR12 rates of at least 93%. In contrast, genotype 3 naïve patients showed more benefit from the combination of PEG-IFN plus RBV, and lower rates of SVR12 have been reported in experienced or IFN-intolerant patients, compared to genotype 2. Preliminary experiences and phase II trials with IFN-free regimens based on DAAs combination showed encouraging results also in genotype 1 naïve and null responder patients. In particular, Sofosbuvir in combination with various DAAs, such as Daclatasvir, Ledipasvir or Simeprevir, plus RBV show excellent SVR rates, close to 100%15-17. However, further data are needed to confirm these results. A recent phase III trial showed that the addition of Sofosbuvir to PEGIFN and RBV for 12 weeks could obtain excellent results in genotype 1, 4, 5 and 6 patients (92% of SVR12 in genotype 1a, 82% in genotype 1b, 96% in genotype 4 and 100% in genotype 5/6 patients; NEUTRINO trial13, Table I). Finally, two NS3/4A protease inhibitors, Simeprevir and Faldaprevir, were also tested in genotype 1 patients in association with PEG-IFN and RBV, with inferior SVR12 rates, 80% and 79-80% respectively, than that obtained with Sofosbuvir (QUEST-1 and STARTVERSO-1 phase II trials18,19.

Nevertheless, if data about the efficacy of the new DAAs are exciting, those regarding safety are astounding. The rate of reported adverse events is lower compared to the previous therapeutic regimens; remarkably, Sofosbuvir presents a good profile of tolerability and no hematologic toxicity13, which represented the main limitation of combined PEG-IFN plus RBV therapy and of the first era of DAAs.

What is certain is that, about 20 years after the approval of the first treatment for hepatitis C, we have once again arrived at a starting point. New antiviral drugs, directly acting against the virus particles, are available. Some of them, namely Telaprevir and Boceprevir, disattended the initial promises, revealing low tolerability profiles and limited efficacy according to patients’ genotypes and subsets (e.g. cirrhotics, liver transplanted). New all-oral, IFN-free regimens requiring short treatment duration are on the horizon. Due to the very encouraging results reported so far, the forecast of a future without HCV infection is now credible. It is unknown how much time will it take, but it is reasonable to encourage patients who have a little benefit from the treatments available so far to wait for the new incoming treatments. On the other hand, clinicians have often to deal with the willingness of their patients to be healed. The major limitation of HCV infection treatments disposable so far was the impossibility to offer to every patient the same opportunity to be treated, an opportunity that was extremely dependent on treatment tolerability and on other factors affecting the route through a favorable response. The first months of 2013 have brought great changes, but there is probably still a long way to difficult to treat go before to reach the same efficacy of treatment in every patient with hepatitis C, and what we see is just the tip of a giant iceberg.

––––––––––––––––––––Conflict of InterestThe Authors declare that they have no conflict of interests.

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